WO2018113094A1 - Utilisation d'une structure de type fullerène dans la préparation d'un médicament pour le traitement du diabète et des complications de ce dernier - Google Patents

Utilisation d'une structure de type fullerène dans la préparation d'un médicament pour le traitement du diabète et des complications de ce dernier Download PDF

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WO2018113094A1
WO2018113094A1 PCT/CN2017/075445 CN2017075445W WO2018113094A1 WO 2018113094 A1 WO2018113094 A1 WO 2018113094A1 CN 2017075445 W CN2017075445 W CN 2017075445W WO 2018113094 A1 WO2018113094 A1 WO 2018113094A1
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fullerene
soluble
oil
water
diabetes
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Chinese (zh)
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王春儒
甄明明
李雪
白春礼
李慧
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Beijing Fullcan Biotechnology Co Ltd
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Beijing Fullcan Biotechnology Co Ltd
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Priority claimed from CN201611180065.4A external-priority patent/CN108201542A/zh
Priority claimed from CN201611180063.5A external-priority patent/CN108201541A/zh
Application filed by Beijing Fullcan Biotechnology Co Ltd filed Critical Beijing Fullcan Biotechnology Co Ltd
Publication of WO2018113094A1 publication Critical patent/WO2018113094A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/44—Elemental carbon, e.g. charcoal, carbon black
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention also requires the Chinese Academy of Sciences Institute of Chemistry and Beijing Funakan Biotechnology Co., Ltd. to submit to the Chinese Patent Office, the application number is CN201611179710.0, and the invention name is "water-soluble fullerene structure in the preparation of drugs for treating diabetes.
  • the priority of the Chinese Patent Application the entire disclosure of which is incorporated herein by reference.
  • the invention also requires the application of the Chinese Academy of Sciences and Beijing Funakan Biotechnology Co., Ltd. to the Chinese Patent Office, the application number is CN 201611180063.5, and the invention name is "fullerene structure in the preparation of drugs for enhancing insulin sensitivity".
  • the priority of the Chinese Patent Application the entire contents of which is incorporated herein by reference.
  • the invention belongs to the field of medicine and relates to the application of fullerene structure in preparing medicines for treating diabetes and its complications, in particular to oil-soluble fullerene structure or water-soluble fullerene structure in preparing medicine for treating diabetes and its complications. Application in .
  • Insulin is a protein hormone secreted by islet beta cells stimulated by endogenous or exogenous substances such as glucose, lactose, ribose, arginine, glucagon, and the like. Insulin is the only hormone in the body that lowers blood sugar, and it also promotes the synthesis of glycogen, fat and protein.
  • Diabetes (DM) is a metabolic disease characterized by hyperglycemia, which is mainly caused by saccharide, protein, and fat metabolism disorders caused by at least one of insulin secretion deficiency and impaired insulin biological activity. Diabetes is divided into type 1 diabetes, type 2 diabetes, and gestational diabetes. Type 1 diabetes is mainly caused by adolescents. It is insulin-dependent diabetes; type 2 diabetes is adult-onset diabetes, which occurs after 35-40 years old, accounting for more than 90% of diabetic patients. Its main feature is relatively insufficient insulin or insulin resistance, and its degree of harm is also the greatest.
  • Diabetes Long-term blood sugar increases cause great harm to human life health and safety, such as: it can cause damage to large blood vessels and micro-vessels and endanger the heart, brain, kidney, peripheral nerves, eyes, feet, etc., causing various complications of diabetes, such as diabetes. Nephropathy, retinopathy, diabetic neuropathy, diabetic foot disease, diabetic skin lesions, atherosclerosis and its associated coronary heart disease, stroke, intermittent pain in lower extremities, and so on. According to the World Health Organization, there are more than 100 complications of diabetes, which is the most known complication to date.
  • Insulin resistance refers to a decrease in the sensitivity of the target organ of insulin action to insulin action, that is, a state in which a normal dose of insulin produces a lower than normal biological effect, which is manifested by the fact that the body tissue cannot respond to insulin.
  • glucose-utilized cells are unable to recognize insulin, resulting in a decrease in blood glucose and a decrease in insulin sensitivity.
  • insulin resistance syndrome as: 1 insulin resistance; 2 impaired glucose tolerance; 3 blood pressure ⁇ 160/90 mmHg; 4 triglycerides ⁇ 1.7 mmol / L; 5 centripetal obesity; 6 body mass index BMI > 30 kg /m2; 7 waist to hip ratio, male > 0.9, female > 0.85; 8 hyperuricemia; 9 microalbuminuria.
  • An individual with diabetes or impaired glucose tolerance or insulin resistance, and at the same time having more than two of the above nine items, can be defined as insulin resistance syndrome.
  • Insulin resistance is the main pathological feature of type 2 diabetes and is associated with many diabetic complications, such as diabetic nephropathy, eye disease, podiatric disease, and cardiovascular disease. The study found that insulin resistance is closely related to these diseases, improving insulin resistance and increasing insulin sensitivity have great significance for the treatment of these diseases.
  • Fullerenes are another allotrope of carbon other than graphite, diamond and amorphous carbon. This type of substance refers to a cage structure composed of carbon atoms. The most abundant molecules are C 60 , then C 70 and C 84 , followed by C 76 , C 78 , C 82 , etc. with relatively small contents.
  • the inside of the carbon cage of fullerenes is a cavity structure, the internal cavity can embed different atoms, ions or clusters of atoms, which is called embedded fullerene, such as La@C 60 , indicating La embedded.
  • embedded fullerene such as La@C 60 , indicating La embedded.
  • the image expresses the meaning of embedded.
  • the fullerene structure of the active ingredient for treating diabetes and its complications involved in the present invention can effectively lower blood sugar in a relatively short period of time, significantly increase glucose tolerance, increase insulin sensitivity, and reduce insulin resistance, thereby fundamentally Treatment of diabetes-induced liver and kidney damage, increased blood viscosity, difficult to heal wounds, cardiovascular and cerebrovascular diseases and other complications.
  • the present invention provides the following technical solutions:
  • the invention also provides a method of treating diabetes and its complications comprising administering to a subject in need of treatment for diabetes and its complications an effective amount of a fullerene structure comprising at least one selected from the group consisting of Active ingredients of the lower group: oil-soluble fullerenes, oil-soluble inlaid metal fullerenes, oil-soluble fullerenes and oil-soluble inlaid metal fullerenes, water-soluble a fullerene, a water-soluble inlaid metal fullerene, a water-soluble fullerene and the water-soluble inlaid metal fullerene composition, a pharmaceutically acceptable ester of the above six or above A pharmaceutically acceptable salt.
  • a fullerene structure comprising at least one selected from the group consisting of Active ingredients of the lower group: oil-soluble fullerenes, oil-soluble inlaid metal fullerenes, oil-soluble fullerenes and oil-soluble inlaid metal fullerenes, water-soluble a fullerene,
  • the present invention also provides a pharmaceutical composition for treating diabetes and its complications, comprising at least one fullerene structure selected from the group consisting of oil-soluble fullerenes, oil-soluble inlaid metal fullerenes, and a composition of oil-soluble fullerenes and the oil-soluble inlaid metal fullerenes, water-soluble fullerene a olefin, a water-soluble inlaid metal fullerene, a water-soluble fullerene, and a water-soluble inlaid metal fullerene composition, a pharmaceutically acceptable ester of the above six, and the above six A pharmaceutically acceptable salt; the pharmaceutical composition further comprising at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and a pharmaceutically acceptable excipient.
  • the oil-soluble fullerene comprises a fullerene having an outer surface of the carbon cage coated with an oil solution.
  • the oil-soluble inlaid metal fullerene comprises an inlaid metal fullerene having an outer surface of the carbon cage coated with an oil solution.
  • the oil solution may be a single component oil or a mixed oil formed of different oil solutions.
  • vegetable oils such as olive oil, linseed oil, sunflower oil, corn germ oil, soybean oil, etc., also include animal fats such as squalane.
  • the fullerene coated with an oil solution on the outer surface of the carbon cage is obtained by oil-soluble modification of the raw material fullerenes, the carbon cage
  • the inlaid metal fullerene having an outer surface coated with an oil solution is obtained by oil-soluble modification of a metal fullerene embedded in a raw material.
  • the oil-soluble modification is to disperse at least one of a raw material fullerene and a raw material inlaid metal fullerene in the oil solution to obtain The oil-soluble modified liquid;
  • the specific dispersion means that the mixture of the raw material and the oil solution may be subjected to ball milling or ultrasonication, and then the precipitate is removed by centrifugation, and then the supernatant liquid is obtained by filtration.
  • the concentration of the active ingredient in the oil-soluble modified liquid is 0.01-100 mg/mL, and the disclosure of the range should be regarded as the disclosure of all the values in the range.
  • the selected ones are 0.01-10 mg/mL, 10-20 mg/mL, 20-30 mg/mL, 30-40 mg/mL, and the like.
  • 0.05-1000 mg of fullerene raw material and/or embedded metal fullerene raw material are dispersed per 1 ml of the oil solution.
  • the disclosure of this range should be considered as a disclosure of all values in the range, optionally 0.05-1 mg, 0.05-10 mg, 0.05-100 mg, and the like.
  • the mixture is subjected to ball milling or sonication for 30 min to 15 h.
  • the above-mentioned application, method or pharmaceutical composition, after ball milling or ultrasonication, before centrifugation, further comprises the step of allowing the mixture to be stored in a cool, dry, dark, and allowed to stand for a certain period of time.
  • a certain time refers to 2h-24h.
  • the water-soluble fullerene comprises one or more selected from the group consisting of: (1) the outer surface of the carbon cage is modified with a hydrophilic group. Fullerene; (2) fullerenes surrounded by hydrophilic biomolecules on the outer surface of the carbon cage; (3) fullerenes supported by a biocompatible carrier material; (4) formed by self-assembly Water-soluble supramolecular system fullerene.
  • the water-soluble inlaid metal fullerene comprises one or more selected from the group consisting of: (1) the outer surface of the carbon cage is modified with a pro Water-incorporated metal fullerenes; (2) inlaid metal fullerenes surrounded by hydrophilic biomolecules on the outer surface of the carbon cage; (3) inlaid by a biocompatible carrier material Metal fullerenes; (4) Self-assembled metal-filled fullerene formed by self-assembly of a water-soluble supramolecular system.
  • the hydrophilic group includes one or more of a hydroxyl group, a carboxyl group, a thiol group, and an amino group.
  • the water-soluble inlaid metal fullerene comprises water-soluble hydroxylated Gd@C 82 ; the water-soluble fullerene comprises water-soluble hydroxylation C 60 or water-soluble hydroxylated C 70 .
  • the hydrophilic bio-small molecule comprises at least one of an amino acid and a peptide chain.
  • the biocompatible carrier material comprises at least one of a liposome and a cell membrane carrier.
  • the biocompatible carrier material is a pharmaceutical carrier commonly used in medicine, including at least one of a liposome and a cell membrane carrier.
  • the polymer micelle is polyglycolide polyethylene glycol (PEG-PLGA), polylysine or chitosan; the protein is albumin or transferrin.
  • the water-soluble fullerene is obtained by water-soluble modification of a raw material fullerene; the water-soluble inlaid metal fullerene It is obtained by water-soluble modification of the metal fullerene embedded in the raw material.
  • the method of water-soluble modification is any one of the following methods: (1) a method of surface modifying a hydrophilic group generally in the action of a base
  • the solution is carried out by a solid-liquid or liquid-liquid reaction, in particular, mixing at least one of the raw material fullerenes and the raw material embedded metal fullerenes with hydrogen peroxide and a base (the alkali may specifically be sodium hydroxide or potassium hydroxide)
  • the reaction is further washed with ethanol and then dialyzed to obtain a water-soluble hydroxy derivative corresponding to the starting material. If it is desired to obtain a water-soluble aminated derivative, the hydroxide in the above step may be replaced with aqueous ammonia.
  • At least one of raw material fullerenes and raw material embedded metal fullerenes may be mixed with at least one of polyethylene glycol, polyvinyl pyrrolidone and cyclodextrin and ball-milled or Ultrasonic or the like can obtain a coated water-soluble fullerene structure corresponding to the raw material, such as polyethylene glycol-coated fullerene and/or polyethylene glycol-coated inlaid metal fullerene, polyethylene Pyrrolidone-coated fullerene and/or polyvinylpyrrolidone-coated inlaid metal fullerenes.
  • the above application, method or pharmaceutical composition is weighed 50 to 300 mg of C 60 or C 70 or Gd@C 82 solid, 5 to 30 ml of 20 to 40% hydrogen peroxide, and 2 to 20 ml of 1 M to 3 M.
  • the alkali solution is mixed at 50 to 100 ° C until the corresponding C 60 or C 70 or Gd@C 82 solid is completely dissolved.
  • the proportional relationship between the substances is expressed. In practice, it is not limited by the specific reaction scale of 50-300 mg, 5-30 ml and 2-20 ml, and can be expanded according to the ratio.
  • the raw material fullerene comprises one or more cage structures consisting of carbon atoms of the formula C 2m , 30 ⁇ m ⁇ 60, for example ; C 60 , C 70 , C 84 , etc.
  • the inlaid metal fullerene raw material comprises M@C 2n , M 2 @C 2n , MA@C 2n , M 3 N@C 2n , M One or more of 2 C 2 @C 2n , M 2 S@C 2n , M 2 O@C 2n and M x A 3-x N@C 2n , wherein: M and A both represent metal elements and M And A is selected from any one of a lanthanide metal element, Sc, and Y, 30 ⁇ n ⁇ 60; 0 ⁇ x ⁇ 3.
  • N represents a nitrogen element
  • C represents a carbon element
  • S represents a sulfur element
  • lanthanide metal elements include La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
  • Gd@C 82 For example: Gd@C 82 .
  • the diabetes is type 1 diabetes or type 2 diabetes.
  • the diabetic complication is a complication caused by type 1 diabetes or a complication caused by type 2 diabetes.
  • the diabetic complication includes diabetic cardio-cerebral vascular disease, optionally cardiovascular and cerebrovascular diseases caused by microvascular and/or macrovascular diseases, such as: arteries Atherosclerosis; diabetic nephropathy; diabetic skin diseases such as: diabetic ulcers, Difficulty in wound healing; hyperviscosity caused by diabetes; diabetic neuropathy, such as: stroke; diabetic eye complications, such as: retinopathy; diabetic foot.
  • microvascular and/or macrovascular diseases such as: arteries Atherosclerosis; diabetic nephropathy; diabetic skin diseases such as: diabetic ulcers, Difficulty in wound healing; hyperviscosity caused by diabetes; diabetic neuropathy, such as: stroke; diabetic eye complications, such as: retinopathy; diabetic foot.
  • the treating diabetes complications include: 1) making the blood glucose elevation caused by diabetes tend to normal; 2) concentrating the size of the islets and the number of islet cells Normal; 3) regulate insulin secretion, reduce insulin resistance, increase insulin sensitivity, make glucose tolerance and insulin tolerance tend to normal; 4) treat coronary heart disease caused by diabetes; 5) make liver and kidney index abnormalities caused by diabetic nephropathy tend to normal (Hepatic and kidney indicators include: alanine aminotransferase, aspartate aminotransferase, serum creatinine, urea nitrogen), which significantly reduces urine protein; 6) accelerate wound healing; 7) reduce blood viscosity increase caused by diabetes; 8) lower blood lipids (blood lipid index) Including: total cholesterol, triglycerides, high and low density lipids; 9) treatment of diabetic foot; 10) treatment of diabetic retinopathy, diabetes-related uveitis and diabetic cataract; 11) significantly reduced glycated hemoglobin; 12) reduce the glycosylation product (
  • the drug or the pharmaceutical composition may be a tablet, a pill, a powder, a lozenge, a sachet, a cachet, an elixir, a suspending agent, Formulations of emulsions, solutions, syrups, aerosols, ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions or sterile packaging powders.
  • the method of preparing an active ingredient into a pharmaceutical or pharmaceutical composition in the present invention can be prepared by a method known to those skilled in the art to provide an immediate release, sustained release or delayed release of the active ingredient after administration to a subject, for example:
  • the active ingredient can be mixed with the carrier, diluted with the carrier or enclosed in a carrier.
  • some examples suitable as carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starch, resins, Acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methylcellulose, methylparaben And propyl ester, talc, magnesium stearate and liquid paraffin.
  • the medicament or the above pharmaceutical composition in the above application may additionally comprise a lubricant, a wetting agent, an emulsifying and suspending agent, a preservative, a sweetener or a flavoring agent. And other additives.
  • the subject is a human or an animal
  • the animal can be a mammal such as a mouse, a guinea pig, a rat, a dog, a rabbit, a monkey, or the like.
  • the active ingredient is administered at a dose of from 1 mg/kg/d to 1000 mg/kg/d, optionally from 1 to 100 mg/kg/d, and from 10 mg/kg/d to 100 mg/ Kg / d, 1-20mg / kg / d, 1-10mg / kg / d, the course of application can be 5 days - 30 days, depending on the condition can be taken short-term or long-term use; the active ingredient can be administered orally, injection ( Such as: intravenous injection or intraperitoneal administration. After the injection, the active ingredient enters the body and directly acts through the blood circulation without permeation.
  • the amount of the medicament used is small and the curative effect is high; the oral intake is filtered and absorbed by the digestive system, and the side effects are smaller and the curative effect is remarkable.
  • the concentration of the active ingredient in the drug or the pharmaceutical composition is 0.01-100 mg/mL, optionally 0.01-10 mg/mL, 0.01-20 mg/mL, 0.01-30 mg/mL, 0.01-40 mg/mL; when the drug or the pharmaceutical composition is present in a solid form, The concentration of the active ingredient in the drug or the pharmaceutical composition is from 0.01 to 50 mg/g, alternatively from 0.01 to 10 mg/g, from 0.01 to 20 mg/g, from 0.01 to 30 mg/g, from 0.01 to 40 mg/g.
  • the water-soluble fullerene and/or water-soluble inlaid metal fullerene is in the formulation at a concentration of 0.01-100 mg/mL;
  • the oil-soluble fullerene and/or oil-soluble inlaid metal fullerene is present in the formulation at a concentration of from 500 ppm to 10,000 ppm (mg/kg).
  • treatment includes its generally accepted meaning, which includes preventing, preventing, inhibiting, ameliorating, and slowing, halting, or reversing the development of a symptom or a desired condition.
  • the invention encompasses both therapeutic and prophylactic administration.
  • active ingredient refers to oil-soluble fullerenes, oil-soluble inlaid metal fullerenes, and oil solubility.
  • a composition of fullerene and the oil-soluble inlaid metal fullerene, a water-soluble fullerene, a water-soluble inlaid metal fullerene, the water-soluble fullerene, and the water-soluble The composition of the metal fullerene embedded, the pharmaceutically acceptable ester of the above six or at least one of the pharmaceutically acceptable salts of the above six.
  • the effective amount can be determined by the participating diagnostician as a result of known techniques by those skilled in the art and in similar circumstances. In determining the effective amount or dose of the active ingredient to be administered, the participating diagnostician should consider a variety of factors including, but not limited to, the mammalian species; volume, age, and general health.
  • raw material fullerene as used in the present invention means a fullerene which is not subjected to water-soluble modification or oil-soluble modification, that is, a fullerene body.
  • inlaid metal fullerene in the raw material means an inlaid metal fullerene which is not subjected to water-soluble modification or oil-soluble modification, that is, an inlaid metal fullerene body.
  • the specific contents, concentrations, etc. of the water-soluble fullerene, the water-soluble metal fullerene, the oil-soluble fullerene or the oil-soluble metal fullerene in the present invention are quantitatively limited.
  • the specific content and concentration of the corresponding fullerene body or the embedded metal fullerene body, for example, the concentration of the water-soluble fullerene in the preparation is 0.01-100 mg/mL, which means that water solubility can be detected.
  • the concentration of the fullerene bulk carbon cage in the fullerene is 0.01-100 mg/mL in the preparation; for example, the content of fullerene coated with the oil solution on the outer surface of the carbon cage is 100 ⁇ M means that the oil solution is The content of the fullerene bulk carbon cage was 100 ⁇ M.
  • metal fullerenes and embedded metal fullerenes can be quantitatively determined by inductively coupled plasma optical emission spectrometry (ICP).
  • the oil-soluble fullerene structure or the water-soluble fullerene structure of the active ingredient maintains a complete carbon cage structure, and the oil-soluble fullerene structure has fat-soluble characteristics, which enter the body and pass through digestion and absorption into the blood circulation. Or through direct organ penetration into various organs; water-soluble fullerene structure plays a role in the body to the various organs with blood circulation.
  • the active ingredient enters the pancreas, improves the microenvironment of pancreatic islets in the pancreas and pancreas, corrects the structure of the islets, reduces the functional damage of the pancreas, reduces the damage of islet ⁇ cells, facilitates the normal secretion of insulin from the pancreas, and reduces insulin resistance, thereby reducing The role of blood sugar; the active ingredient enters the liver, kidney and other organs, reducing the oxidation of sugar, protein and lipids, reducing the glycation end products, thereby alleviating various complications of diabetes.
  • the active ingredient oil-soluble fullerene structure or water-soluble fullerene structure has a good effect of scavenging free radicals and can improve the body's redox level, and the active ingredients can be quickly metabolized, no toxicity to internal organs , has good biocompatibility.
  • the treatment of diabetes in the prior art requires long-term effects of the drug, and the active ingredient in the present invention
  • the fullerene structure can effectively lower blood sugar in a relatively short period of time. After taking 5-30 days, the blood sugar level can be significantly reduced, and the glucose tolerance can be significantly increased, thereby fundamentally treating diabetes and its caused liver and kidney damage, Complications such as cardiovascular disease and slow wound healing.
  • the oil-soluble fullerene structure can be used in combination with a hypoglycemic agent, which can reduce side effects and improve complications while lowering blood sugar.
  • the oil solution coated with the oil-soluble fullerene structure of the present invention can select a vegetable oil or animal oil which has no side effects and has a nutritive effect.
  • olive oil is a natural health care and cosmetic effect.
  • Vegetable oil which promotes the development of bones and nervous system, can be cosmetic, anti-aging, and can prevent cardiovascular diseases.
  • Figure 1 is a photograph of an aqueous solution of Gd@C 82 (OH) n material in Example 2.
  • Fig. 2 is a graph showing changes in serum superoxide dismutase and catalase after administration of mice for 2 weeks in Example 3.
  • Fig. 3 is a graph showing the content of malondialdehyde in serum after administration of mice for 2 weeks in Example 3.
  • Fig. 4 is a graph showing the detection of alanine aminotransferase and aspartate aminotransferase in liver injury indexes after administration of mice in Example 3 for 2 weeks.
  • Fig. 5 is a graph showing the detection of urea nitrogen and serum creatinine in the kidney injury index after administration of the mice in Example 3 for 2 weeks.
  • Figure 6 is a graph showing changes in urinary protein after administration of mice for 2 weeks in Example 3.
  • Figure 7 is a graph showing the metabolic distribution of Gd@C 82 (OH) n material in vivo for 24 h in vivo.
  • Figure 8 is an electron spin nuclear magnetic resonance (ESR) image of the Gd@C 82 (OH)n material in Example 5, wherein the smooth line indicates a blank control and the non-smooth line indicates the addition of Gd@C 82 (OH)n.
  • ESR electron spin nuclear magnetic resonance
  • Figure 9 is a graph showing changes in fasting blood glucose during the treatment in Example 6.
  • Figure 10 is a graph showing the glucose tolerance curve after two weeks of treatment in Example 6.
  • Figure 11 is a bar graph of the area under the curve within 120 minutes in the glucose tolerance test after two weeks of treatment in Example 6.
  • Figure 12 is a graph showing changes in the content of catalase in mice after two weeks of treatment in Example 6.
  • Figure 13 is a graph showing changes in the content of malondialdehyde in mice after two weeks of treatment in Example 6.
  • Figure 14 is a graph showing changes in blood glucose in the insulin resistance test in Example 7.
  • Figure 15 is a graph showing the contents of triglyceride and total cholesterol in mice after administration for 2 weeks in Example 7.
  • Figure 16 is a graph showing the content of glucose transporter-4 in mouse adipocytes after administration for 2 weeks in Example 7.
  • the experimental methods used in the following examples are conventional methods unless otherwise specified.
  • the materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
  • the raw material Gd@C 82 solid powder used in the following examples was purchased from Xiamen Funa New Material Technology Co., Ltd., with a molecular weight of 1141 and a purity of 99.1%.
  • the raw material C 60 solid powder used in the following examples was purchased from Xiamen Funa New Material Technology Co., Ltd., with a molecular weight of 720 and a purity of 99%.
  • the raw material C 70 solid powder used in the following examples was purchased from Xiamen Funa New Material Technology Co., Ltd., with a molecular weight of 840 and a purity of 99%.
  • the present application will olive oil soluble and C 60 fullerene prepared by the above method referred C 60 - Olive oil, olive oil and oil-soluble C 70 fullerene prepared by the above method referred C 70 - olive oil, the Olive oil and Gd@C 82 oil-soluble fullerenes prepared as described above are abbreviated as Gd@C 82 - olive oil.
  • the content of the modified fullerene or the raw material inlaid metal fullerene in the oil-soluble modified liquid is 0.8 mg/ml.
  • the hydroxylated water-soluble hollow fullerene or the hydroxylated water-soluble inlaid metal fullerene obtained after dialysis contains more liquid, and is concentrated by ultrafiltration centrifugation, but whether or not concentrated, raw materials
  • the water-soluble modification of metal fullerenes or metal-filled fullerene in the raw material has been completed, and whether or not the concentration is carried out does not affect the use thereof, and the water-soluble fullerene or the water-soluble inlaid metal fullerene is adjusted to a suitable use.
  • the concentration can be.
  • Fig. 1 is a photograph of a 200 ⁇ M aqueous solution of Gd@C 82 (OH) n , which can be seen to be clear and transparent, and has good water solubility.
  • the invention adopts a mature high-fat fed STZ (streptozotocin)-induced type 2 diabetes model to study the therapeutic effect of oil-soluble fullerenes on diabetic complications.
  • STZ streptozotocin
  • mice Twenty-four male ICR mice purchased from 7-8 weeks were purchased from Peking University Experimental Animal Center and randomly divided into 4 groups, 6 in each group. 6 male ICR mice in 1 group were used as healthy mice without diabetes.
  • the control group ie, the blank group
  • the other 18 were used to form a diabetes model.
  • the diabetes model was formed as follows: First, the mice were fed with high-fat diet for 4 weeks, then fasted for 12 hours, and then quickly injected intraperitoneally with STZ citrate solution. The dose of STZ was 60 mg/kg/d (ie, according to the weight of the mice). Calculated by injecting 60 mg of STZ per 1 kg), once a day for 3 consecutive days.
  • the model shows symptoms of complications such as diabetic nephropathy, diabetic liver disease, diabetic vascular disease, and slow wound healing in a certain period of time.
  • the experimental mice were divided into 4 groups, 6 in each group, and 6 healthy mice in the step (1) with no diabetes (ie, the blank group) were used as the group A, and the administration treatment was the administration of the drugs used in the group D and the like.
  • Volume of physiological saline; 6 diabetic model mice formed in step (1) were randomly selected as a model group (abbreviated as group B), and the administration treatment was to apply the same volume of physiological saline as the drug used in group D; 1) Diabetic model mice formed in 6 rats as olive oil group (referred to as group C), and applied with the same volume of pure olive oil as the drug used in group D; randomized diabetic mice formed in step (1)
  • Six of the C 60 - olive oils prepared in Example 1 were applied as an experimental group (referred to as Group D).
  • the ABCD group was administered by intragastric administration once a day for 2 weeks.
  • the dose of C 60 - olive oil in group D was 20 mg/kg/d.
  • SOD Superoxide dismutase
  • CAT Hydrogenase
  • MDA malondialdehyde
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • Tr serum creatinine
  • BUN urea nitrogen
  • SOD and CAT can reflect the level of redox in the body; SOD is an important antioxidant enzyme in the body, widely distributed in various organisms, it has special physiological activity, is the primary substance in the body to scavenge free radicals; CAT It is an enzyme scavenger that decomposes H 2 O 2 into molecular oxygen and water, and removes hydrogen peroxide from the body, thereby protecting cells from H 2 O 2 poisoning. MDA is a free radical metabolite, and its content increases when more free radicals are produced.
  • mice in the AD group were bled by eyeballs.
  • the blood samples were allowed to stand at room temperature for 1 h, centrifuged at 3500 rpm for 15 min, and the supernatant serum was aspirated.
  • the absorbance at 550 nm was determined by spectrophotometry.
  • the content of catalase (SOD) was determined by measuring the absorbance at 405 nm, and the content of catalase (MDA) was calculated by measuring the absorbance at 532 nm.
  • FIG. 2 shows that superoxide dismutase and catalase are significantly lower in mice with diabetes than in healthy mice (see comparison between model group and blank group), after C 60 - olive oil treatment Superoxide dismutase and catalase in mice tend to normal levels, as shown in the experimental group.
  • Figure 3 shows that malondialdehyde is significantly higher in mice with diabetes than in healthy mice (see comparison between model group and blank group), whereas mice treated with C 60 -olive oil have lower malondialdehyde content.
  • synthetic free radicals decrease. Changes in these three indicators indicate that the level of redox in the mouse is regulated, and the corresponding oxidative stress and its complications are also reduced.
  • Detection indicators are indicators of liver function, and urea nitrogen and serum creatinine are indicators of renal function.
  • mice in the AD group were bled by eyeballs.
  • the blood samples were allowed to stand at room temperature for 1 h, centrifuged at 3500 rpm for 15 min, and the supernatant serum was aspirated.
  • the serum was tested by an automatic blood biochemistry instrument to detect the alanine aminotransferase. (ALT), aspartate aminotransferase (AST), serum creatinine (Cr) And the content of urea nitrogen (BUN).
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • Cr serum creatinine
  • BUN urea nitrogen
  • Figure 4 shows that the index of alanine aminotransferase and aspartate aminotransferase in mice with diabetes is much higher than that of normal mice (see comparison between model group and blank group), but after C 60 - olive oil treatment The values of alanine aminotransferase and aspartate aminotransferase in mice were normal, and there was no significant difference between the olive oil group and the model group, indicating that oil-soluble fullerenes can improve liver function damage caused by diabetes.
  • Figure 5 shows that both urea nitrogen and serum creatinine in diabetic mice are significantly higher than those in normal mice (see comparison between model group and blank group), but urea nitrogen in mice after C 60 - olive oil treatment The serum and creatinine values were normal, and there was no significant difference between the olive oil group and the model group, indicating that oil-soluble fullerenes can improve renal function damage caused by diabetes.
  • mice Two weeks after administration of mice in the AD group, the mice were placed in a metabolic cage for 24 hours. The urine of the mice was collected and the volume of urine was measured. The concentration of urinary protein was measured by Elisa kit. The urine protein concentration was multiplied by the urine volume to obtain the 24 hour urine protein discharge.
  • Urine protein is an important indicator of diabetic nephropathy.
  • Figure 6 shows that the urine output of mice with diabetes is much higher than that of normal mice within 24 hours (see comparison between model group and blank group), but The urine protein excretion of mice treated with C 60 - olive oil was significantly reduced, while the olive oil group was not significantly different from the model group, indicating that oil-soluble fullerenes significantly ameliorated the development of diabetic nephropathy.
  • Plasma viscosity is one of the important factors affecting the viscosity of whole blood. Increased plasma viscosity will cause the whole blood viscosity to increase.
  • mice after two weeks of administration were subjected to whole blood through the eyeball, and the rheological properties of the blood were examined under a normal condition by a blood rheometer.
  • the plasma viscosity of the blank group was about 1.5 mPa/s
  • the viscosity of the model group was increased to 2.0 mPa/s
  • the viscosity of the experimental group was significantly reduced to 1.7 mPa/s.
  • the oil-soluble fullerene composition can alleviate vascular diseases such as an increase in blood viscosity caused by diabetes.
  • the invention uses C 60 - olive oil as an example to treat STZ-induced diabetic mice with high fat feeding, and finds that the oil-soluble fullerene structure has a good alleviating effect on diabetic complications.
  • Example 4 In vivo metabolism of water-soluble inlaid metal fullerene Gd@C 82 (OH) n
  • Example 5 Water-soluble inlaid metal fullerene Gd@C 82 (OH) n scavenging free radical ability detection
  • the present invention detects the ability of water-soluble inlaid metal fullerene Gd@C 82 (OH) n to scavenge free radicals by electron spin resonance spectroscopy (ESR).
  • ESR electron spin resonance spectroscopy
  • Example 6 Treatment of diabetes by water-soluble inlaid metal fullerene Gd@C 82 (OH) n
  • the experimental animals were db/db diabetic mice purchased from the Nanjing Animal Model Center and cited from the Jackson Laboratory in the United States.
  • This mouse is a widely used animal model of type 2 diabetes, which is a mouse model in which the leptin receptor gene defect leads to the development of diabetes after obesity.
  • the spontaneous mutation of the leptin receptor (Lepr) causes polyphagia, Diabetes, polyuria and other symptoms.
  • Db/db mice developed hyperinsulinemia on 10 to 14 days, obesity in 3 to 4 weeks, and hyperglycemia in 4 to 8 weeks.
  • the experimental animals were divided into 3 groups of 6 each.
  • Six db/m non-diabetic mice were used as a blank group (abbreviated as group A), and the administration was performed by administering an equal volume of physiological saline with the drug used in group C; 6 db/db mice were randomly selected as the model group.
  • group B the administration of the drug was the same volume of physiological saline as that used in group C; 6 db/db mice were randomly selected as Gd@C 82 (OH) n experimental group (referred to as group C)
  • the administration treatment was Gd@C 82 (OH) n prepared by the method of Example 2.
  • the AC group was administered by intraperitoneal administration.
  • the mice of each group entered the 10th week and started to administer once a day for two weeks.
  • group C Gd@C 82 (OH) n was given.
  • the dose is 10 mg/kg/d.
  • the present invention demonstrates the therapeutic effect of water-soluble inlaid metal fullerene Gd@C 82 (OH) n on diabetes by db/db diabetes mellitus changes in blood glucose and glucose tolerance test, and improves blood oxidation in vivo by blood biochemistry. Restore level.
  • Fig. 9 is a graph showing changes in fasting blood glucose. It can be seen from Fig. 9 that the fasting blood glucose of the diabetic mice treated with saline only in the model group is much higher than that of the experimental group.
  • the diabetic mice treated with @C 82 (OH) n were also much higher than the fasting blood glucose of the non-diabetic mice in the blank group, while the experimental group was fasted to the diabetic mice treated with Gd@C 82 (OH) n . Blood sugar tends to be normal.
  • Glucose tolerance test was performed after 2 weeks of administration. After fasting for 12 hours, the blood glucose level was measured as 0 min blood glucose, then the glucose solution was administered at a dose of 2 g/kg of mouse body weight, and then blood glucose was measured at 15, 30, 60, and 120 min, respectively, and the glucose tolerance curve was obtained. And the area under the curve (AUC) was calculated to characterize the glucose tolerance of the mice. Results As shown in Fig. 10 and Fig.
  • the diabetic mice treated with Gd@C 82 (OH) n in the experimental group had better control of blood glucose than the diabetic mice treated with normal saline in the model group, and the experimental group The AUC was significantly smaller than that of the model group, indicating that Gd@C 82 (OH) n can better treat diabetes, increase glucose tolerance, and enhance the ability of mice to regulate and control blood sugar.
  • CAT is an enzyme scavenger that decomposes H 2 O 2 into molecular oxygen and water, removing hydrogen peroxide from the body, thereby protecting cells from H 2 O 2 poisoning.
  • MDA is a free radical metabolite, and its content increases when more free radicals are produced.
  • mice in each group were bled by the eyeball, and the blood sample was allowed to stand at room temperature for 1 hour, centrifuged at 3500 rpm for 15 min, and the upper serum was aspirated, and the absorbance at 405 nm was measured by spectrophotometry to obtain catalase.
  • the content of (CAT) is determined by measuring the absorbance at 532 nm to obtain the content of malondialdehyde (MDA), and the detection of the above two substances can be detected by a commercially available corresponding kit.
  • MDA malondialdehyde
  • mice were db/db diabetic mice purchased from the Nanjing Animal Model Center and cited from the Jackson Laboratory in the United States. This mouse is a mouse model of leptin receptor gene deficiency leading to development of type 2 diabetes after obesity. db/db mice develop hyperinsulinemia on 10 to 14 days, and obesity in 3 to 4 weeks, 4 to 8 weeks. Hyperglycemia occurs. It has the characteristic of type 2 diabetes and produces typical insulin resistance.
  • the experimental animals were divided into 4 groups of 6 each.
  • Six db/m non-diabetic mice were used as the blank group (abbreviated as group A), and the administration was performed by administering the same volume of physiological saline as the group C drug; 6 db/db mice were randomly taken as the model group ( Referred to as group B), the administration of the drug is the same volume of physiological saline as that of group C; 6 db/db mice are randomly taken as the C 70 (OH) n experimental group (referred to as group C), and the drug is administered.
  • the treatment was to apply C 70 (OH) n prepared according to the method of Example 2; 6 db/db mice were randomly taken as the C 60 - olive oil experimental group (abbreviated as group D), and the administration treatment was performed according to the administration.
  • the mice of each group entered the 10th week and started to be administered daily. One time, continuous administration for two weeks, and the doses of groups C and D were 10 mg/kg/d.
  • the insulin resistance test was performed 2 weeks after the administration. After fasting for 4 hours, the blood glucose was measured, and the blood glucose level was counted as 0 minutes. Then, the insulin was administered to the patient at a dose of 1 U/kg of the mouse body weight, and then the blood glucose was measured at 15, 30, 60, and 120 minutes after the gavage. Insulin tolerance curve. The results are shown in Figure 14.
  • the blood glucose of the non-diabetic mice in the blank group decreased the fastest in the first 15 min; while the db/db diabetic mice in the model group who had diabetes but received only saline treatment were There was almost no drop in blood glucose during the first 15 minutes, and the average rate of decline during the entire 120-min period was also slow; compared with the model group, db/db diabetic mice in the C 70 (OH) n experimental group and the C 60 -olive oil experimental group Blood sugar was reduced, and the average rate of blood glucose reduction was also significantly faster than the model group, especially the first 15 min, thus demonstrating that mice with diabetes were injected after administration of C 70 (OH) n and C 60 - olive oil. After insulin can lower blood sugar, and the sensitivity to insulin increases, and the resistance to insulin is weakened.
  • mice Two weeks after the administration, the mice were bled by eyeballs, allowed to stand at room temperature for 1 hour, centrifuged at 3500 rpm for 15 min, and the supernatant serum was aspirated, and triglyceride TG and total cholesterol TC were measured by an automatic blood biochemistry analyzer.
  • the triglyceride and total cholesterol of the model group were significantly increased relative to the blank group, whereas the contents of the triglyceride and cholesterol of the mice after administration of C70 (OH) n and C60 -olive oil were relatively In the model group, it is obviously reduced and tends to be normal. It is shown that C 70 (OH) n and C 60 - olive oil can increase the sensitivity of mice to insulin and the resistance to insulin is weakened.
  • insulin resistance causes a decrease in the content of glucose transporter-4.
  • the present invention treats db/db mice with C 60 - olive oil composition and C 70 (OH) n as an example, and found that water-soluble fullerenes and oil-soluble fullerenes can make mice sensitive to insulin. Increased, the resistance to insulin is weakened.

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Abstract

L'invention concerne l'utilisation d'une structure de type fullerène dans la préparation d'un médicament pour le traitement du diabète et des complications de ce dernier. La structure de type fullerène comprend au moins un ingrédient efficace sélectionné dans le groupe constitué d'un fullerène soluble dans l'huile, d'un métallofullerène endohédral soluble dans l'huile, d'une composition du fullerène soluble dans l'huile et du métallofullerène endohédral soluble dans l'huile, d'un fullerène soluble dans l'eau, d'un métallofullerène endohédral soluble dans l'eau, d'une composition du fullerène soluble dans l'eau et du métallofullerène endohédral soluble dans l'eau, d'esters de qualité pharmaceutique des six ingrédients ci-dessus, ou de sels de qualité pharmaceutique des six ingrédients ci-dessus.
PCT/CN2017/075445 2016-12-19 2017-03-02 Utilisation d'une structure de type fullerène dans la préparation d'un médicament pour le traitement du diabète et des complications de ce dernier Ceased WO2018113094A1 (fr)

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CN201611180063.5 2016-12-19
CN201611179710 2016-12-19
CN201611180065.4 2016-12-19
CN201611180065.4A CN108201542A (zh) 2016-12-19 2016-12-19 油溶性富勒烯在制备治疗糖尿病并发症的药物中的应用
CN201611180063.5A CN108201541A (zh) 2016-12-19 2016-12-19 富勒烯结构在制备增强胰岛素敏感性的药物中的应用
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035441A2 (fr) * 2003-10-10 2005-04-21 C Sixty Inc. Compositions de fullerenes substitues et utilisation de ces compositions en tant qu'antioxydants
CN1832719A (zh) * 2003-05-30 2006-09-13 奈尔·伯兰古洛夫 含有富勒烯簇的化妆品组合物
CN1961027A (zh) * 2004-03-31 2007-05-09 日本化药株式会社 新的水溶性富勒烯、其生产方法和含有该富勒烯的活性氧发生器
CN101098684A (zh) * 2004-12-07 2008-01-02 维生素C60生化学研究公司 自由基疾病预防治疗用组合物
CN104997646A (zh) * 2015-07-09 2015-10-28 北京福纳康生物技术有限公司 一种富勒烯油溶性溶液及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1832719A (zh) * 2003-05-30 2006-09-13 奈尔·伯兰古洛夫 含有富勒烯簇的化妆品组合物
WO2005035441A2 (fr) * 2003-10-10 2005-04-21 C Sixty Inc. Compositions de fullerenes substitues et utilisation de ces compositions en tant qu'antioxydants
CN1961027A (zh) * 2004-03-31 2007-05-09 日本化药株式会社 新的水溶性富勒烯、其生产方法和含有该富勒烯的活性氧发生器
CN101098684A (zh) * 2004-12-07 2008-01-02 维生素C60生化学研究公司 自由基疾病预防治疗用组合物
CN104997646A (zh) * 2015-07-09 2015-10-28 北京福纳康生物技术有限公司 一种富勒烯油溶性溶液及其制备方法

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